Mechanisms that control initiation of the adaptive immune responses is one of the fundamental questions of immunology. Innate immune recognition plays a critical role in the activation of immune responses. In particular, recognition of infection by a family of Toll-like receptors (TLRs) is a crucial step in the induction of T cell activation. TLRs induce maturation of dendritic cells. Induction of expression of co-stimulatory molecules on dendritic cells is a critical step in naive T cell activation. Activation of T cells is also controlled by suppressor T cells, including CD4+CD25+ regulatory T cells (Tregs). Tregs prevent activation of autoreactive T cells and thus prevent the development of a variety of autoimmune diseases. However, Tregs should not interfere with immune responses directed at pathogens. Because pathogens are recognized by the TLR family, we hypothesize that TLR-mediated recognition should lead to a blockade of Treg-mediated suppression to allow protective immune responses to infecting pathogens. Our preliminary studies provide strong evidence that this is indeed the case. The goal of this proposal is to address multiple aspects of this hypothesis.